Cognitive Dysfunction: An Update From the 1st International Workshop on HIV & Aging

This is part of a series of articles summarizing presentations from the 1st International Workshop on HIV & Aging, which took place in Baltimore, Md., from Oct. 4 to Oct. 5, 2010. Jump to the table of contents to see the other articles in this series.

The CHARTER cohort in the United States is a huge study that includes HIV-positive people who are an average of 43 years of age. Findings discussed at this conference revealed that almost half of those CHARTER participants had some sort of mild cognitive function. In a conference call with the study investigators, I asked how this finding compares with a similar HIV-negative population. They said that mild cognitive declines would be expected in 10 percent to 20 percent of HIV-negative people, which would mean that HIV almost doubles the rate. It seems that CD4 nadir was one of the strongest predictors of cognitive decline.

Avindra Nath, M.D., reviewed data on how HIV can possibly affect neurons even in the presence of complete HIV viral control after HAART initiation. Nath's discussion focused on Tat, which is short for "transactivator of transcription"; it's a regulatory gene within HIV that accelerates the production of more HIV virus. In fact, Tat is crucial to HIV, because HIV completely fails to replicate itself without it.

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Tat protein is also toxic, so the large amounts of Tat released into the blood by HIV-infected cells are no help for the body. It can be absorbed by cells that are not infected with HIV, and can cause cell death (via a process called apoptosis) in uninfected "bystander" T cells, which can assist a person's progression toward AIDS.

In addition, Tat increases immune activation, which enables immune cells to more easily get inside of neurons and affect their functioning. Immune activation causes a state of "high alert" in which the immune system struggles to produce responses that could control HIV or other proteins that are identified as "foreign." There is a broad consensus among researchers that this chronic state of immune activation contributes to the virus's ability to cause certain health issues, including cognitive dysfunction. However, while there are some hypotheses about how HIV (or certain proteins) causes chronic immune activation, the precise mechanisms are still under investigation.

Following Nath's discussion, Marcus Kaul, Ph.D., presented data on a genome-wide analysis of HIV from the NeuroAIDS study. A protein produced by HIV called gp120 has been linked to disruptions in metabolism, inflammation and a condition known as HIV-Associated Neurocognitive Disorder (HAND). Kaul also presented data on the increase in neurofilaments in HIV-positive people, as well as increased amyloid plaque deposition in neurons, which grows as HIV infection progresses. He mentioned that Tat and gp120 prevent the "clean up" of these amyloid plaques. This plaque buildup is also worsened by the immune activation that has been found in samples of cerebrospinal fluid of HIV-positive people regardless of whether they have an undetectable viral load. Luckily, this accumulation of plaque in neurons is not similar to that seen in Alzheimer's patients, so it may not lead to the same dramatic decreases in cognitive function.

Although antiretroviral therapy can significantly increase resting cerebral blood flow (rCBF) in HIV-positive people, it does not return to normal, according to results of small cross-sectional and longitudinal studies. Using imaging techniques, these studies found that "functional brain demands in HIV-positive subjects were equivalent to those of HIV-negative subjects who were 15-20 years older."

At this conference, a study from 2006 was also mentioned, in which scientists at the National Institutes of Health found that HIV infection breaks down barriers in the intestine that normally prevent intestinal bacteria from entering the bloodstream. The blood of HIV-infected people was found to contain markedly elevated levels of lipopolysaccharide (LPS), a component of certain bacteria that is normally confined to the intestine but "leaks" out due to HIV infection. LPS may also be associated in immune activation and cognitive decline. Studies using prebiotics (nutrients that help friendly bacteria grow in the gut) and anti-inflammatory compounds have been proposed to determine if these approaches can stem the LPS leakage and improve LPS-related immune activation.

In a separate presentation, Scott Letendre, M.D., spoke about a microtubule-associated protein called Tau. High levels of phosphorylated Tau (pTau) have been associated with aging-related cognitive problems (such as dementia and Alzheimer's) in HIV-negative people. Unfortunately, pTau levels appear to be considerably higher in HIV-positive people compared to HIV-negative people of the same age, according to Letendre. In fact, it is estimated that HIV increases pTau to levels that are comparable to HIV-negative people who are 20 years older. pTau levels also appear to continue to rise in HIV-positive people on HAART even though their CD4 count is increasing.

Letendre spoke about a study in which a test called the Memory for Intentions Screening Test was administered to HIV-positive people. The test assesses a person's "prospective memory," or their ability to remember to do something they intend to do in the future. This study found that HIV-positive people had worse prospective memory than normal for their age -- but that their overall neurocognitive performance was no worse than average.

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